The present invention relates to controlled-release dosage forms comprising zolpidem or salts thereof.
EP 173 928 discloses an oral pharmaceutical controlled release preparation which has a biphasic release profile of a pharmacologically active agent, comprising a core containing the active agent and a coating applied thereon, wherein the coating consists of a film-forming polymer which is insoluble in water and gastro-intestinal fluids and a water-soluble pore-creating material also including the active agent.
EP 361 910 discloses granules which have a spray-dried substance carrying an adsorbed pharmaceutical and a layer comprising a pharmaceutically acceptable excipient and a pharmaceutical.
GB 2 245 492 discloses an orally administrable programmed release (i.e. release after a predetermined delay) pharmaceutical preparation comprising a core coated with a hydrophobic material and a surfactant.
Zolpidem is a suitable short acting hypnotic for the controlled-release dosage form according to the present invention. Zolpidem is a hypnotic from the therapeutical class of imidazopyridines. It is administrated orally by means of a tablet or other solid dosage form. Zolpidem acts rapidly. Indeed pharmacokinetic and pharmacodynamic data show that zolpidem has both a rapid absorption and onset of hypnotic action. Its bioavailability is 70% following oral administration and demonstrates linear kinetics in the therapeutical dose range, which lies between 5 and 10 mg in conventional forms, peak plasma concentration is reached at between 0.5 and 3 hours, the elimination half-life is short, with a mean of 2.4 hours and a duration of action of up to 6 hours.
For reasons of simplicity, in the absence of contrary indication, within the whole description xe2x80x9czolpidemxe2x80x9d or the xe2x80x9cdrugxe2x80x9d means zolpidem per se as well as its salts. The preferred salt of zolpidem is zolpidem hemitartrate.
Up to now, according to the rapidity of action of zolpidem, only immediate release dosage forms were developed, which disintegrate rapidly in the gastrointestinal tract, dissolve in the fluid of the gastrointestinal tract and undergo systemic absorption, where zolpidem, can exert its pharmacological effect and induce sleep of the patient.
The new dosage forms according to the present invention enable to sustain release over a period compatible with the desired time of sleep and the time needed for elimination of the drug from the human body to a sufficiently low level.
Therefore, as a first object, the present invention provides controlled-release dosage forms comprising zolpidem or salts thereof adapted to release over a predetermined time period, according to a biphasic profile of dissolution, where the first phase is an immediate release phase and the second phase is a prolonged release phase.
The xe2x80x9ctotal amount of drugxe2x80x9d means the quantity by weight of the drug comprised in the whole dosage form according to the invention.
The first phase or immediate release phase is that part of the dissolution profile from 0 to 30 minutes in a suitable in vitro dissolution test. A suitable dissolution test is for example one of the method described in example 1: method where measurement is carried out in a type II dissolution apparatus according to U.S. pharmacopoeia in aqueous buffer at 37xc2x0 C., or variations on this as well known to one who is skilled in the art. The proportion of the drug dissolved during this phase is the proportion of the total amount of the drug which is dissolved at 30 minutes. In an advantageous embodiment of the dosage forms according to the present invention 90% or more of that part of the drug allotted for the first phase is dissolved in 20 minutes and more preferably in 15 minutes.
The second phase or prolonged release phase is that part of the dissolution profile which is after 30 minutes, measured in a suitable in vitro dissolution test, such as described in example 1. The present invention then proposes dosage forms of the drug whose complete dissolution time for the second phase is between 2 and 6 hours, and preferably between 2.25 and 3.5 hours.
The profile of the second, prolonged release phase is defined by the percentage released at times T1, T2, and T3, defined as follows.
T1 is the beginning of the second phase of drug release, and is equal to 30 minutes.
T3 is near the end of the second phase of drug release, and is the time at which 85% of the drug allotted for the second phase is released.
T2 is the time at which 50% of the drug allotted for the second phase is released. For example, if 50% of the total amount of drug is released at 30 minutes, there is 50% remaining for the second phase of release. T3 is therefore the time for 92.5% dissolution [50%+0.85xc3x9750%], and T2 is the time for 75% dissolution.
The second phase can represent a profile of release proportional to the square root of time, according to the equation proposed by T. Higuchi, J.Pharm.Sci. 52, 1145 (1963), sometimes called matrix release, where (T2xe2x88x92T1)=0.35(T3xe2x88x92T1). More advantageously the second phase can be first-order release where (T2xe2x88x92T1)=0.37(T3xe2x88x92T1). Still more advantageously the second phase can represent a profile of order zero or a sigmoidal profile. A profile of order zero is one where the release rate is constant or near-constant, and (T2xe2x88x92T1)=0.59(T3xe2x88x92T1). A sigmoidal profile is one where the release rate in the second phase accelerates so (T2xe2x88x92T1) greater than 0.59(T3xe2x88x92T1) . Profiles intermediate between these different types are also covered.
The rapid release in the first phase induces the immediate sleep of the patient and the second phase allows the drug blood level to be maintained at or below the peak level, but higher than the level obtained with an immediate release dosage form, at the same time after dosing, with the objective of maintaining sleep.
The present invention then proposes dosage forms of zolpidem or a salt thereof whose complete dissolution time, defined as the time for release of 90% of the total amount of drug is between 2 and 6 hours and preferably between 2.25 and 3.5 hours.
40 to 70% of the total amount of drug can be released during the immediate release phase, preferably between 50 and 60%.
An example of such an in vitro release profile is given in FIG. 1, where 60% of the total amount of drug is released during the immediate release phase, and the second phase is zero order with 90% of the total amount of drug dissolved in 3 hours. Further examples of such profiles are shown in FIG. 2, where 50% of the total amount of drug is dissolved during the immediate release phase, and the second phase release is according to three other types of profile; release proportional to square root of time (matrix release), first order release, and a sigmoidal release profile.
As a second object, the present invention provides controlled-release dosage forms of zolpidem or salts thereof, characterised in that they comprise two kinds of pharmaceutical entities of drug: one immediate release entity and one prolonged release entity. The drug dissolved during the immediate release phase (before 30 minutes) is contained within the immediate release entity, and that liberated in the prolonged release phase (after 30 minutes) is contained within the prolonged release entity.
Small quantities of the drug in a formulation for rapid release can be retained in the formulation and thus may be released at a time after 30 minutes from the beginning of the dissolution, and are thus included in the prolonged release phase. Similarly, small quantities of the drug incorporated in the prolonged release pharmaceutical entity may be released before 30 minutes, and thus form part of the immediate release phase.
According to the present invention, the proportion of the drug contained within the immediate release entity and dissolved within 30 minutes is at least 90%. And the proportion of the drug contained within the prolonged release entity and released within 30 minutes is comprised between 0 and 35%, and preferably between 0 and 25%.
Among dosage forms able to match the requirement of a biphasic profile and to comprise the two kinds of pharmaceutical entities defined above, the following may be cited: capsules, tablets, multilayer tablets, multicoated tablets.
The immediate release entity shall be understood in the present invention as a single pharmaceutical immediate release unit like for example an immediate release tablet or pellet, or several such units formulated into a capsule or a tablet; as an immediate release matrix in a tablet; as an immediate release layer, that can be incorporated in a multilayer tablet; as an immediate release coating layer in a multicoated tablet or pellet.
The prolonged release entity shall be understood in the present invention as a pharmaceutical prolonged release unit such as, for example, a prolonged release tablet or pellet, or several such units formulated into a capsule or a tablet; as a prolonged release layer, that can be incorporated in a multilayer tablet; as a prolonged release core or a prolonged release coating layer in a multicoated tablet; as prolonged release pellets within a disintegrating tablet.
Dosage forms where the immediate release entity and the prolonged release entity are administered simultaneously but separately are also encompassed in the present invention.